Description

• Renal tubular acidosis (RTA) is composed of a group of disorders characterized by an inability of the kidney to resorb bicarbonate/secrete hydrogen ions, resulting in hyperchloremic, normal anion gap acidosis. Renal function (glomerular filtration rate [GFR]) must be normal or near normal.
• Several types have been identified:
  • Type I (distal) RTA: Inability of the distal tubule to acidify the urine. Due to impaired hydrogen ion secretion, increased backleak of secreted hydrogen ions, or impaired sodium reabsorption (interfering with the generation of negative luminal charge required for hydrogen/potassium secretion). Urine pH >5.5.
  • Type II (proximal) RTA: Defect of the proximal tubule in bicarbonate (HCO₃) reabsorption. Proximal tubular HCO₃ reabsorption absent; plasma HCO₃ concentration stabilizes at 12–18 mEq/L due to compensatory distal HCO₃ reabsorption. Urine pH <5.5 unless plasma HCO₃ brought above reabsorptive threshold (1).
  • Type III RTA: Extremely rare autosomal–recessive syndrome with features of both type I and type II (may be due to carbonic anhydrase II deficiency).
  • Type IV RTA (hypoaldosteronism): Due to aldosterone resistance/deficiency that results in hyperkalemia. Urine pH usually <5.5.

Epidemiology

• Predominant age: All ages
• Predominant sex: Male > Female (with regard to type II RTA with isolated defect in bicarbonate reabsorption)

Risk Factors

• Type I RTA: Autosomal-dominant/-recessive. May occur in association with other genetic diseases (e.g., Ehlers-Danlos syndrome, hereditary elliptocytosis, or sickle cell nephropathy). The autosomal-recessive form is associated with sensorineural deafness.
• Type II RTA: Autosomal-dominant form is rare. Autosomal-recessive form is associated with ophthalmologic abnormalities and mental retardation. Occurs in Fanconi syndrome, which is associated with several genetic diseases (e.g., cystinosis, Wilson disease, tyrosinemia, hereditary fructose intolerance, Lowe syndrome, galactosemia, glycogen storage disease, and metachromatic leukodystrophy).
• Type IV RTA: Some cases are familial, such as pseudohypoaldosteronism (PHA) type I (autosomal dominant).

General Prevention

Careful use/avoidance of causative agents

Etiology

• Type I RTA:
  • Genetic: Autosomal dominant, autosomal recessive associated with sensorineural deafness
  • Sporadic
  • Other familial disorders: Ehlers-Danlos syndrome, glycogenosis type III, Fabry disease, Wilson disease
  • Autoimmune diseases: Sjögren syndrome, rheumatoid arthritis (RA), systemic lupus erythematous (SLE)
  • Hematologic diseases: Sickle cell disease (hyperkalemic), hereditary elliptocytosis
  • Medications: Amphotericin B, lithium, ifosfamide, foscarnet, K⁺-sparing diuretics (amiloride, triamterene), trimethoprim, pentamidine
  • Toxins: Toluene, glue
  • Hypercalciuria, diseases causing nephrocalcinosis
  • Vitamin D intoxication
  • Medullary cystic disease
  • Obstructive uropathy (hyperkalemic)
  • Hypergammaglobulinemic syndrome
  • Chronic pyelonephritis
  • Chronic renal transplant rejection
  • Leprosy
  • Hepatic cirrhosis
  • Malnutrition
• Type II RTA:
  • Familial disorders (cystinosis, tyrosinemia, hereditary fructose intolerance, galactosemia, glycogen storage disease type I, Wilson disease, Lowe syndrome, inherited carbonic anhydrase deficiency)
  • Sporadic
  • Multiple myeloma, other dysproteinemic states
  • Amyloidosis
  • Heavy-metal poisoning (e.g., cadmium, lead, mercury, copper)
  • Medications: Acetazolamide, ifosfamide, tenofovir, sulfanilamide, outdated tetracycline, topiramate, aminoglycosides
  • Interstitial renal disease
  • Paroxysmal nocturnal hemoglobinuria
  • Defects in calcium metabolism (hyperparathyroidism)
• Type IV RTA:
  • Medications: NSAIDs, ACE inhibitors, angiotensin receptor blockers, heparin/LMW heparin, ketoconazole, calcineurin inhibitors (tacrolimus, cyclosporine) (2)
  • Diabetic nephropathy
  • Nephrosclerosis due to hypertension
  • Tubulointerstitial nephropathies
  • Primary adrenal insufficiency
  • PHA (end-organ resistance to aldosterone):
    • PHA type 1
    • PHA type 2 (Gordon's syndrome)

Commonly Associated Conditions

• Type I RTA in children: Hypercalciuria leading to rickets, nephrocalcinosis
• Type I RTA in adults: Autoimmune diseases (Sjögren syndrome, RA, SLE), hypercalciuria
• Type II RTA: Fanconi syndrome (generalized proximal tubular dysfunction resulting in glycosuria, aminoaciduria, hyperuricosuria, phosphaturia, bicarbonaturia)
• Type II RTA in adults: Multiple myeloma, carbonic anhydrase inhibitors (acetazolamide)
• Type IV RTA: Diabetic nephropathy